by A groundbreaking study published in the journal Nature Aging has revealed the potential of senolytics in alleviating brain aging and coronavirus disease 2019 (COVID-19) neuropathology. Senolytics are a class of drugs designed to selectively remove senescent cells – cells that cease dividing and contribute to aging and age-related conditions.
COVID-19 patients commonly experience various neurological complications, and autopsied brain tissue transcriptomic data suggests a link between severe COVID-19 cases and cognitive decline associated with brain aging. Although prior research has implicated senescent cells in neurodegeneration and cognitive decline in aging mice and in vivo neuropathology models, their role in human brain tissue aging and COVID-19 pathology in the central nervous system remains uncertain.
To address this knowledge gap, researchers decided to investigate the effects of senolytics on physiological brain aging and COVID-19 neuropathology. The team started by generating human brain organoids (BOs) from embryonic stem cells and aging them for eight months to replicate the process of brain aging. The BOs were then treated with senolytics, including the dasatinib-quercetin (D+Q) combination, ABT-737, and navitoclax, over the course of one month with a two-week interval between treatments.
The study found that senolytic interventions significantly reduced the activity of senescence-associated β-galactosidase (SA-β-gal), a marker of senescent cells. This was further confirmed by higher levels of lamin B1, a nuclear marker that is downregulated in senescence, in the treated BOs. The researchers also identified the cell types involved in senescence phenotypes by co-immunolabeling with a senescence marker, p16. They discovered that over three-fourths of p16-positive cells co-immunostained with astrocytes, while approximately 15% co-localized with mature neurons. These two cell populations represented the majority of p16-positive cells.
RNA sequencing analysis revealed several positive outcomes from the senolytic treatments. Notably, the upregulation of lamin B1 messenger RNA (mRNA) levels across all senolytic interventions, as well as the consistent suppression of 81 senescence-related mRNAs. Moreover, aging clock predictions based on whole-transcriptome sequencing showed that D+Q treatment effectively reversed the gene expression age of nine-month-old organoids to levels observed in eight-month-old organoids. These gene expression changes induced by D+Q treatment correlated with pro-longevity interventions, such as rapamycin administration and caloric restriction.
The researchers also examined brain tissue from COVID-19 decedents and found a significant increase in the number of p16-positive cells compared to non-COVID-19 controls. Additionally, the study exposed human brain organoids to various viral pathogens to investigate the contribution of neurotropic viruses to aging-induced neuropathology. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affected neurons, microglia, and neural progenitors. Among the SARS-CoV-2 variants tested, the Delta variant induced the most potent senescence.
Interestingly, the study demonstrated that senescence induced by SARS-CoV-2 infection triggered secondary senescence in non-infected cells through a bystander effect. Senescence was also observed in organoids infected with Japanese encephalitis virus (JEV), Zika virus (ZIKV), or Rocio virus (ROCV). Further analysis of transcriptomic changes in COVID-19 patients and SARS-CoV-2-infected brain organoids revealed the enrichment of known senescence and aging pathways in the common gene set.
Furthermore, the study evaluated the impact of senolytic interventions on SARS-CoV-2-infected organoids. Senolytics significantly reduced the number of cells with senescence activity in brain organoids five days after infection, with a more prominent effect observed in organoids infected with the Delta variant. Pretreatment with senolytics before infection also resulted in a significant reduction in virus-induced senescence. The study identified two populations of neurons that experienced significantly higher incidence of senescence following infection, and senolytic interventions prevented cellular senescence in these populations.
To validate the findings in vivo, the researchers infected K18-hACE2 mice, which express the human angiotensin-converting enzyme 2 (hACE2) under the regulation of the keratin 18 (K18) promoter, with the SARS-CoV-2 Delta variant. The mice were then treated with senolytics that can cross the blood-brain barrier, such as D+Q, navitoclax, and fisetin. Treatment with fisetin or D+Q significantly improved the survival of infected mice. Senolytic interventions also reduced COVID-19-related features, viral gene expression, and inflammatory senescence-associated secretory phenotype (SASP) in the brains of infected mice.
In conclusion, the study provides compelling evidence for the role of cellular senescence in brain aging and COVID-19 neuropathology. The use of senolytics showed promise in reducing cellular senescence and inflammation, improving survival rates, and mitigating COVID-19-related features in brain organoids and infected mice. These findings highlight the therapeutic potential of senolytics in combating brain aging and COVID-19-associated neuropathology, opening up new possibilities for treatment and intervention in these conditions.
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
Money Singh is a seasoned content writer with over four years of experience in the market research sector. Her expertise spans various industries, including food and beverages, biotechnology, chemicals and materials, defense and aerospace, consumer goods, etc.
